Synergistic microbicidal compositions



Nov. 16, 1954' R. D. STAYNER 2,694,663

SYNERGISTIC MICROBICIDAL COMPOSITIONS Filed Sept. 5, 1950 maooc FU/VG/C/DAL ACTIVITY OF QUATER/VARY AMHONIUM GERM/C/DE-AL/(Vl. AROMATIC HYDROCARBON COMPOSITIONS rommo TR/Cl-IOPHYTON ROSACEUM.

I: loooe TEST METHOD NAVY SPEC. /06 0 psooc MAXIMUM EFFECTIVE KILLING DILUTION mooo 0 IO 4O 5O 6O 8O I00 QUATERNARY AMMONIUM GERMICIDE I00 90 so 70 so so 40 30 -2o 10' o ALKYL AROM'ATIC HYDROCARBON PERCENT COMPOSITION l/VVENTOR RICHARD D. STAYNER SYNERGESTIC MicRontcmAL COMPOSITIONS Richard D. Stayner, Albany, Calif., assignor to California Research Corporation, San Francisco, Calif., 21 corporation of Delaware Application September 5, 1950, Serial No. 183,279

4 Claims. (Cl. 167-3 This invention relates to new and improved compositions for the control of micro-organisms, such as bacteria, fungi, algae, protozoa and the like. More particularly, the invention relates to compositions which comprise a quaternary ammonium germicide and a neutral hydrocarbon oil promoter.

Prior to my invention quaternary ammonium compounds per se have been used as microbicides or germicides, the terms being here intended synonymously to designate agents effective in the control of micro-organisms in general. The activity of such compounds varies widely with different types of organic cation radicals contained therein. As a consequence, a great amount of experimental effort and expense has been necessary to develop more eflicient types of quaternary ammonium germicide materials. These quaternary ammonium compounds are usually costly and in many cases are characterized by a notably poor efliciency in the control of micro-organisms, particularly spore-forming bacteria, fungi, molds and the like. i

It is an object of my invention to provide novel quaternary ammonium compositions which are economical to produce and more efiicient than the quaternary ammonium compounds themselves as microbicides or germicides, particularly toward spore-forming bacteria, fungi, molds, and the like.

Other objects and advantages of my invention will be apparent from the disclosure which hereinafter appears.

I have found that quaternary ammonium germicides and neutral hydrocarbon oil promoters of the type hereinafter described may be combined in such proportions as to produce strongly microbicidal or germicidal compositions having activity even exceeding that of the quaternary ammonium compounds themselves. This resultant improvement in efiiciency is highly unexpected, since the neutral hydrocarbon oil promoters as hereinafter described are, of themselves, largely non-germicidal, particularly toward spore-forming bacteria, fungi, etc., against which even the quaternary ammonium compounds are relatively inelfective.

The production of these novel and more highly elfective microbicidal compositions according to my invention requires only the simplest of procedures. It involves none of the complicated experimentation that is necessary when improvement of the germicidal efiiciency of a quaternary ammonium compound is attempted through modification of the hydrophobic cationic portion of the molecule. I

The extraordinary effect of my discovery is illustrated graphically by the curve shown in the figure of the accompanying drawing. Upon reference to this curve it will be seen that when certain substantial amounts of quaternary ammonium compound are combined with a representative neutral hydrocarbon oil promoter of the type hereinafter more particularly described, the resultant composition possesses germicidal activity against a representative fungus far in excess of the quaternary alone.

The quaternary ammonium germicides used in the compositions of my invention can be any of several various types which fall within the generic term. These compounds are generally characterized by the formula wherein at least one of the radicals, R1, R2, R3 and R4, attached to the nitrogen atom is a hydrophobic aliphatic,

States Patent ice unsaturated aliphatic, cyc'loaliphatic, aryl, araliphatic or aliphaticaryl radical of from 6 to 26 carbon atoms. The hydrophobic radicals may be long-chain alkyl, long-chain alkenyl, cycloalkyl, long-chain alkoxyaryl, long-chain alkylaryl, halogen-substituted long-chain .alkylaryl, longchain alkylphenoxyalkyl, arylalkyl, etc., in nature. The remaining radicals on the nitrogen atom other than the hydrophobic radicals may be substituents of hydrocarbon structure ordinarily containing a total of no more than about 12 carbon atoms. Various compounds of these types are more fully illustrated in the disclosure which follows. Mixtures of quaternaries may be used as well as the single compounds.

In brief, the enhancing agents or promoters in the compositions according to my invention may be any neutral hydrocarbon oil. They should be neutral in the sense that they have no free electric charge and are neither acidic nor basic. They should also be substantially immiscible with water. Suitable neutral hydrocarbon oil promoters may be aliphatic, unsaturated aliphatic, cycloaliphatic, aryl, or aliphatic aryl in structure and should contain from about 6 to 24 carbon atoms and preferably 12 to 18 carbon atoms. The promoters may be pure single compounds falling within the preceding general description or may be comprised of mixtures of such compounds, said mixtures being either synthesized or derived as such from natural sources, such as pctroleum.

The proportions of the quaternary ammonium germicide and the neutral hydrocarbon oil promoter are critical 'to the compositions according to my invention. However, these critical proportions may vary over a wide range from a minimum amount of promoter just sufficient to promote the germicidal activity of the quaterr nary ammonium compound up to a maximum amount of about per cent by weight of the composition. A very marked improvement is obtained with proportions of promoter ranging from about 2 to about 8 per cent, while compositions containing the promoter in proportions of about 4 to about 6 per cent exhibit the greatest increase in germicidal activity.

The improved quaternary ammonium germicide compositions of my invention are suitably prepared by adding the neutral hydrocarbon oil promoter to the quaternary ammonium compounds in suitable proportions and mixing them together. The promoters may also be present in the germicidal mixture as unreac'ted materials used in the process of preparing the iiuaternary ammonium germicide, Such compositions, however, are not generally as effective as those prepared by adding the desired promoter to the quaternary ammonium compound per se. Various means for mixing and handling the materials will be obvious to persons skilled in the .art from this disclosure, and as such are contemplated by my invention.

As more specific examples of the various quaternary ammonium compounds used in my novel compositions alkyl ammonium halides such as cetyl trimethyl ammonium bromide, octadecyl dimethyl ethyl ammonium bromide, octadecenyl dimethyl ethyl ammonium bromide, dioctadecyl dimethyl ammonium chloride, etc. are contemplated. Other related quaternary ammonium salts which also may be used are the alkylaryl ammonium halides such as the long-chain alkyl dimethyl benzyl ammonium chlorides in general, including octadecyl dimethyl benzyl ammonium bromide, alkyl dimethyl dichlorbenzyl ammonium chloride, lauryl dimethyl benzyl ammonium chloride, and the like. N-alkylmorpholinium and N-alkylpyridinium quaternary ammonium salts as illustrated by N-cetylpyridinium bromide, N-myristylpicolinium chloride, N-dodecyl-N-methylmorpholinium methosulfate, etc. are also suitable. Another type of quaternary ammonium salt which is contemplated is that wherein the molecule contains an ether linkage as exemplified by compounds such as para-'tertiaryoctylphenoxyethoxyethyl dimethyl benzyl ammonium chloride and the like. Quaternary ammonium salts having oxygen in the form of amide or ester linkages, such as N-i(laurylcolaminoformylmethyl) pyridinium chloride and the like. Still other satisfactory types of quaternary ammonium compounds are those containing a su'lfo'n- Patented Nov. 16, 1954 amide group such as 2-phenyl-3-p-suIfamido-phenyl-5- undecyltetrazolium chloride, etc. Another type of very effective quaternary ammonium germicide is that characterized by a substituted aromatic nucleus as in the case of lauryloxyphenyl trimethyl ammonium chloride, cetylaminophenyl trimethyl ammonium methosulfate, dodecylbenzyl trimethyl ammonium chloride, chlorinated dodecylbenzyl trimethyl ammonium chloride, lauryl dimethyl chlorobenzyl ammonium chloride, cetyl dimethyl nitrobenzyl ammonium chloride, and the like.

Although any of the above types of quaternary ammonium germicides are ordinarily satisfactory in the compositions according to my invention those which are particularly effective are the long-chain alkyl dimethyl benzyl quaternary ammonium salts, the alkylphenoxyalkoxyalkyl dimethyl benzyl quaternary ammonium salts, the N-(acylcolaminoformylmethyl)-pyridinium halides, the long-chain alkyl trimethyl ammonium halides, as well as the long-chain alkylarylmethyl quaternary ammonium compounds.

Lon-chain alkylarylmethyl quaternary ammonium germicides which are particularly adapted to the novel compositions of my invention belong to the class of quaternary ammonium salts illustrated by the type where R1 is an alkyl group of 8 to 18 carbon atoms, Ar is an aryl hydrocarbon nucleus, R is hydrogen or a methyl radical, m is from 1 to 4, Y is hydrogen or a halogen, n is from 1 to 8, R2, R3 and R4 are substituents of hydrocarbon structure containing a total of no more than 12 carbon atoms, and X is a salt-forming anionic radical which may be the same as Y.

In the above long-chain alkylarylmethyl quaternary ammonium germicide the long-chain alkyl radical R1 can be any alkyl group of from 8 to 18 carbon atoms. When the acyclic alkyl radicals are of a straight chain nature those containing as few as 8 to 10 carbon atoms are found to be very satisfactory. However, when branchedchain structures predominate in the acyclic radical, the most satisfactory groups are those containing from 10 to 18 carbon atoms. Suitable alkyl radicals can be obtained from various sources such as the long-chain olefins of 8 to 18 carbon atoms derived from cracked olefinic petroleum fractions or from Fischer-Tropsch synthesis. A preferred source of long-chain alkyl radicals is the class of acyclic propylene polymers having from 9 to carbon atoms per molecule with from 12 to 15 carbon atoms being still more preferred.

The aryl nuclei of the long-chain alkylaryl quaternary ammonium germicides represented by the above formula can be benzene, toluene, xylene, naphthalene, anthracene, etc., with benzene and toluene being preferred. The N-substituted alkyl radicals in the formula preferably contain from 3 to 10 carbon atoms and may be separate alkyl radicals attached to the nitrogen atom or they may be combined alkyl and cycloaliphatic or aromatic hydrocarbon substituents as in the case of N- ethylpiperidine and pyridine.

Since the cationic portion of the above quaternary ammonium germicides is the active component, the saltforming radicals are not generally regarded as being critical in nature. Any anionic radicals capable of yielding water-soluble salts can be used, such as the halides, sulfates, phosphates, carbonates, nitrites, alkylsulfates, alkylphosphates, formate, acetate, tartrate, and the like. Halide radicals such as chloride and bromide are preferred, and short-chain alkylsulfates such as methosulfate, ethylsulfate, and the like, are among the more satlisfactory alkyl sulfates contemplated as anionic radica s.

The above long-chain alkylarylmethyl quaternary ammonium compounds can be appropriately prepared by chloromethylation of a long-chain alkylary compound to produce the corresponding alkylarylmethyl chloride which may then be condensed with any suitable tertiary amine to get the desired product. The halogenated longchain alkylarylmethyl quaternary ammonium compounds, on the other hand, are conveniently prepared by direct halogenation of a long-chain alkylaryl compound having from 1 to 4 methyl radicals attached to the aryl nucleus. When the halogenation is carried out .in the absence of any halogenation catalysts which might promote substitution of the aryl nucleusa product is derived alkylarylmethyl quaternary ammonium compound.

Promoters, according to my invention, which come within the scope of the previous brief description are, for example, the alkyl aromatic hydrocarbons, such as butyl benzene, dodecyl benzene, octadecyl benzene, dodecyl toluene, nonyl naphthalene, etc. Aliphatic hydrocarbon paraffins, such as mineral oil, neutral oil, etc., are also satisfactory. Petroleum distillates, such as kerosene or various naphthas boiling in the range of from about C. to 500 C. may also be used. 0f the foregoing illustrative neutral hydrocarbon oil promoters or enhancing agents the alkyl aromatic hydrocarbons, such as nonyl benzene, dodecyl benzene, pentadecyl benzene, octadecyl benzene, and mixtures thereof, as well as the corresponding alkyl toluenes, are particularly satisfactory. Alkyl aromatic hydrocarbons having an alkyl radical corresponding in structure to a polypropylene chain are preferred, with those containing an average of from 12 to 15 carbon atoms being even more preferred.

Various mixtures of a representative quaternary ammonium germicide and a neutral hydrocarbon oil promoterwere prepared for testing to illustrate the present invention. Dodecylbenzyl trimethyl ammonium chloride was chosen for its availability as the quaternary ammonium germicide while the neutral hydrocarbon oil selected as a promoter was a dodecyl benzene having a polypropylene type alkyl radical. The mixtures were prepared by placing the quaternary ammonium germicide in a vessel and adding the promoter, following which the ingredients were intimately mixed. The efiicacy of the different quaternary ammonium germicide and promoter compositions containing varying proportions of the quaternary and promoter is illustrated by the regilllts of the tests which are set out in the following ta e.

Table.Fungicia'al activity of quaternary ammonium germzczde-alkyl aromatzc hydrocarbon compositions toward Trichophyton rosaceum gnaterrrary mtn mum Alkyl Aromatic Maximum zgggflg gg Hydr carbon Eflcctive zvl Trilneth'vl (D decyl Ben- Killing Ammonium zene) P' rceut Dilution in Chloride) Per- By Wt Water cent By Wt.

16. 7 83. 3 1, 502 18. 2 81. 8 1. 820 20.0 80. 0 1. 700 22. 2 77.8 2. 220 25.0 75. 0 2. 250 28. 6 71. 4 3. 000 33. 3 66. 7 2, 335 40. 0 60.0 2. 400 50- 0 50. 0 2, 500 55. 5 44. 5 3, 330 62. 5 37. 5 3. 755 71. 4 28. 6 2, 33. 4 16. 6 2, 919 91. 0 9. 0 1, 820 92. 6 7. 4 9, 260 at: ast 99. o 1.0 91900 100.0 0. 0 2, 000

The values for germicidal activity set out in the above table were obtained by determining the maximum effective killing dilutions of the different compositions prepared according to this invention as well as of the pure quaternary ammonium germicide. The maximum efiective killing dilution illustrates the killing power of the different materials against a. representative fungus such as T ricophyton rosaceum and was obtained by the testing method set out in Navy Department Specification 51D6. The higher the effective dilution, the greater the germicidal power of the composition tested.

From the above table of results and reference to the curve in the figure of the accompanying drawing which was obtained by plotting the maximum effective killing dilution against various proportions of quaternary and promoter, the unexpectedly high germicidal activity of compositions according to my invention is readily apparent. It can be seen that my germicidal compositions containing substantial proportions of quaternary ammonium germicides and limited amounts of less than about 80 per cent by weight of promoter are decidedly superior to the quaternary ammonium compound in germicidal efliciency. Compositions of 95% quaternary and promoter are almost ten times better than the pure quaternary itself. Any lowering of germicidal activity, which would ordinarily be expected when a strongly germicidal material such as the quaternary is diluted with a material having no germicidal action as in the case of the neutral hydrocarbon oil promoters of the present invention, is surprisingly absent when proportions according to the teaching of my invention are utilized.

Because of their higher germicidal activity, my novel compositions are more efficacious in most applications than the quaternary ammonium germicides alone. Their greater efiicacy renders them extraordinarily useful in the control of highly resistant micro-organisms such as sporeforming bacteria, fungi, and the like. Various uses include the disinfection of utensils and equipment used in drinking, eating and the preparation of foods, etc. Wearing apparel, bedding, upholstery, and the like, can also be effectively sterilized by the use of my germicidal compositions. Floors and walls as Well as other equipment such as lavatories and toilets in the areas where it is desirable to promote germ-free surroundings can be conveniently disinfected with these germicidal compositions because of their greater germicidal activity. Additional applications, such as their use as antiseptic ingredients in germicidal detergents, ointments, cosmetics, etc., are also indicated.

The germicidal compositions according to my invention may contain various dyes or coloring agents which are compatible with the quaternary ammonium germicides and the neutral hydrocarbon oil promoters in order to improve the general appearance of the compositions. The use of various perfumes and odor masking agents is also contemplated.

In some instances the germicidal compositions of this invention may contain water, as for example, when a composition is prepared by adding the promoter to a 50 per cent aqueous solution of the quaternary ammonium germicide. In the presence of certain amounts of water, as for example amounts exceeding about 30 per cent and less than about 90 per cent of the aqueous quaternary ammonium germicide solution, a separation of the promoter and aqueous quaternary ammonium germicide mixture may occur. Although such separation has no effect on the germicidal activity of my compositions, it will be preferred to maintain the water in amounts of less than about 30 per cent or more than about per cent by weight whenever clear and completely miscible or homogeneous mixtures are desired for the sake of appearances.

The foregoing description and examples of the germicidal compositions according to my invention are intended as illustrative only. Many obvious variations and modifications of the invention will be apparent to those skilled in the art. All such variations and modifications as come within the scope of the appended claims are contemplated by my invention.

I claim:

1. A germicidal composition consisting essentially of from 4 to 6 per cent by weight of dodecyl benzene and from 94 to 96 per cent by weight of dodecylbenzyl trimethyl ammonium chloride.

2. A germicidal composition consisting essentially of from 4 to 6 per cent by weight of dodecyl benzene derived from a propylene tetramer mixture and from 94 to 96 per cent by weight of dodecylbenzyl trimethyl am monium chloride.

3. A germicidal composition consisting essentially of from 2 to 8 per cent by weight of dodecyl benzene. from 98 to 92 per cent by weight of dodecylbenzyl trimethyl ammonium chloride, based on the combined weight of the dodecyl benzene and the dodecylbenzyl trimethyl ammonium chloride, and an amount of water approximately equal in weight to the dodecylbenzyl trimethyl ammonium chloride.

4. A germicidal composition consisting essentially of from 92 to 98 per cent by weight of N-dodecylbenzyl- N,N,N-trimethyl quaternary ammonium chloride and from 2 to 8 per cent by weight of dodecyl benzene.

References Cited in the file of this patent UNITED STATES PATENTS Number Name Date 2,295,504 Shelton Sept. 8, 1942 2,314,111 Tucker Mar. 16, 1943 OTHER REFERENCES Lawrence et al.: J. Am. Pharm. Assn., November 1947, vol. 36, pp. 353-358.

Rawlins et al.: J. Am. Pharm. Assn. (1943), vol. 32, PP- 11-16.

Hyamines 1622 and 10-X, a pamphlet publ. by the Rohm 8: Haas Co., Philadelphia, Pa. (1947), pages 2 to 4. 

4. A GERMICIDAL COMPOSITION CONSISTING ESSENTIALLY OF FORM 92 TO 98 PER CENT BY WEIGHT OF N-DODECYLBENZYLN,N,N-TRIMETHYL QUATERNARY AMMONIUM CHLORIDE AND FROM 2 TO 8 PER CENT BY WEIGHT OF DODECYL BENZENE. 